WO2011093423A1 - (e)-ヒドロキシイミノフェニル酢酸誘導体の製法 - Google Patents
(e)-ヒドロキシイミノフェニル酢酸誘導体の製法 Download PDFInfo
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- WO2011093423A1 WO2011093423A1 PCT/JP2011/051697 JP2011051697W WO2011093423A1 WO 2011093423 A1 WO2011093423 A1 WO 2011093423A1 JP 2011051697 W JP2011051697 W JP 2011051697W WO 2011093423 A1 WO2011093423 A1 WO 2011093423A1
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- 0 CCC[C@](CCCC(C)(*)CC(C)C)C(*)=NO Chemical compound CCC[C@](CCCC(C)(*)CC(C)C)C(*)=NO 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/14—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/14—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a process for producing (E) -hydroxyiminophenylacetic acid derivatives.
- the oxime derivative has a glucokinase (GK) activation action, and is a therapeutic agent for diabetes or chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease or arteriosclerosis, and obesity And / or is known to be useful as a preventive agent (Patent Document 1).
- GK glucokinase
- Patent Document 1 discloses (E) -hydroxyiminophenylacetic acid derivatives (formula IV of Patent Document 1: (Wherein R 1 represents hydrogen or the like, R 2 represents alkylsulfonyl or the like, Z 2 represents alkyl or the like, and A represents aryl or the like) A method for producing an oxime derivative using a compound represented by formula (II) as a production intermediate is disclosed.
- the hydroxyiminophenylacetic acid derivative is obtained as a mixture of geometric isomers, it is isomerized using trifluoroacetic acid (TFA) as a solvent, extracted, and then recrystallized to (E) -hydroxyiminophenylacetic acid.
- TFA trifluoroacetic acid
- a derivative has been produced (Example 1 of Patent Document 1), and development of a safe method for producing an (E) -hydroxyiminophenylacetic acid derivative with a small number of steps has been desired.
- An object of the present invention is to provide an inexpensive and high-yield industrial production method for a hydroxyiminophenylacetic acid derivative with a small number of steps.
- R represents a protecting group for carboxylic acid
- R 1 represents a hydrogen atom or a halogen atom
- R 2 is a halogen atom, cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylthio, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted nonaromatic
- Step a reacting a compound of formula II with hydroxylamine or a salt thereof;
- Step b Formula (Z) -I: (In the formula, each symbol is the same as above.) Isomerizing the compound represented by formula (E) -I in a solvent in the presence of an acid to precipitate crystals of the compound represented by formula (E) -I; and (step c) of the compound represented by formula (E) -I A step of filtering the crystals.
- a method for producing a compound represented by formula VIII or a pharmaceutically acceptable salt thereof comprising the following steps: (Where Q represents cycloalkyl, heterocyclic group, alkyl or alkenyl, R 3 and R 4 independently represent a hydrogen atom, alkoxy, substituted or unsubstituted heterocyclic group, alkoxyalkoxy, substituted or unsubstituted cycloalkyl, cyano, substituted or unsubstituted aryl, substituted or unsubstituted carbamoyl, hydroxy, alkanoyl Represents alkylthio, alkoxycarbonyl, substituted or unsubstituted aryloxy, halogen atom, oxo or substituted or unsubstituted arylcarbonyloxy, Ring T represents a heteroaryl or non-aromatic heterocyclic group, R 5 represents a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted
- Step 1 A step of producing a compound of formula (E) -I comprising the following steps: (Step a) reacting a compound of formula II with hydroxylamine or a salt thereof; (Step b) Formula (Z) -I: (In the formula, each symbol is the same as above.) A step of isomerizing the compound represented by formula (E) -I in a solvent in the presence of an acid to precipitate crystals of the compound represented by formula (E) -I; and (step c) of the compound represented by formula (E) -I Filtering the crystals;
- Step 2 A step of producing a compound represented by the formula V by reacting a compound represented by the formula (E) -I with a compound represented by the formula IV; (Step 3) hydrolyzing the compound represented by Formula V to produce a compound represented by Formula VI; and (Step 4) reacting the compound represented by Formula VI with the compound represented by Formula VII. .
- This production method can be suitably carried out at 0 ° C. to 70 ° C., preferably 0 ° C. to room temperature.
- the acid an inorganic acid or an organic acid can be used, and examples thereof include one or a plurality of acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoromethanesulfonic acid, tosylic acid, mesylic acid, and the like.
- hydrochloric acid, particularly concentrated hydrochloric acid can be suitably used.
- the acid may be present, and it is preferable to add 3 equivalents or more, particularly 5 equivalents or more.
- the solvent is preferably a solvent having a difference in solubility of Compound (E) -I between 40 ° C. to 60 ° C. and 0 ° C. to room temperature, and examples thereof include acetonitrile, alcohol solvents, water, or a mixed solvent thereof.
- the alcohol solvent methanol, ethanol, and isopropanol are preferable, and methanol is particularly preferable.
- the amount of the solvent is preferably such that the compound (E) -I is dissolved at 40 ° C. to 70 ° C. and the crystals are precipitated at 0 ° C. to room temperature.
- the solvent is methanol, 1 to 10 ml / g, particularly 3 to 5 ml / g is preferred.
- compound (Z) -I as a raw material does not have to be pure compound (Z) -I, and may be a mixture of geometric isomers of compound (Z) -I and compound (E) -I.
- Crystal precipitation can be suitably carried out by adjusting the amount of the solvent, adding a solvent having low solubility of compound (E) -I, cooling, and / or adding a seed crystal of compound (E) -I.
- the crystal of compound (E) -I can be obtained with high purity by filtering the solvent. The obtained crystals may be washed with a solvent as appropriate.
- This production method can be suitably carried out by heating to 50 ° C. to 60 ° C. in the presence of an acid and then cooling to 0 ° C. to room temperature.
- Step a In this step, compound (Z) -I and compound (E)-are reacted by reacting compound II with hydroxylamine or a salt thereof (hydrochloride, sulfate, etc.) in a solvent suitable for carrying out step b.
- 1 is a process for producing a mixture of I.
- This reaction can be carried out by any conventional method for converting a ketone to hydroxyimino. It can be carried out in the presence or absence of an acid. This reaction can be suitably carried out at 0 ° C to 70 ° C, preferably 40 ° C to 60 ° C.
- compound II and hydroxylamine or a salt thereof, and other impurities may coexist in the reaction solution.
- Step b This step can be carried out in the same manner as in the production of compound (E) -I from compound (Z) -I.
- This step can be preferably carried out by adding an acid at 40 ° C. to 60 ° C. to the reaction solution obtained in step a, cooling to 0 ° C. to room temperature, and inoculating seed crystals as appropriate.
- Process c The crystal of compound (E) -I can be obtained in high purity by filtering the solvent. The obtained crystals may be washed with a solvent as appropriate.
- Step 1 a step of producing a compound represented by Compound (E) -I;
- Step 2 A step of producing a compound represented by the formula V by reacting a compound represented by the formula (E) -I with a compound represented by the formula IV;
- Step 3 hydrolyzing the compound represented by Formula V to produce a compound represented by Formula VI;
- Step 4 reacting the compound represented by Formula VI with the compound represented by Formula VII. .
- Step 1 can be carried out according to the above-described method for producing compound (E) -I from compound II.
- Steps 2 to 4 can be performed according to the method described in Patent Document 1 as follows.
- reaction with compound IV in which L is a halogen atom, an optionally substituted arylsulfonyloxy or an optionally substituted alkylsulfonyloxy may be carried out using a suitable solvent (acetone, ethanol, THF, dimethyl sulfoxide, DMF, Dioxane, N, N-dimethylacetamide, N-methylpyrrolidone or the like or a mixed solvent thereof) in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride, cesium carbonate or the like.
- a suitable solvent acetone, ethanol, THF, dimethyl sulfoxide, DMF, Dioxane, N, N-dimethylacetamide, N-methylpyrrolidone or the like or a mixed solvent thereof
- a base such as potassium carbonate, potassium tert-butoxide, sodium hydride, cesium carbonate or the like.
- Compound V can be prepared by any conventional method for hydrolyzing alkoxycarbonyl to carboxyl, for example, lithium hydroxide in an appropriate solvent (alcohol solvent such as methanol, ethanol, or THF, dioxane, water, or a mixed solvent thereof), It can be converted to compound VI by hydrolyzing the R group by treatment with sodium hydroxide, potassium carbonate or the like.
- compound V in which R is benzyl can be hydrolyzed by catalytic reduction or the like.
- Stage 4 The reaction from compound VI to compound VIII can be carried out by converting compound VI into a reactive intermediate such as acid chloride or mixed acid anhydride and then reacting with compound VII. Conversion to the acid chloride can be suitably carried out by using thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, triphenylphosphine in the presence of carbon tetrachloride, etc.
- the conversion can be performed by using diphenyl phosphoryl chloride, diethyl phosphorocyanidate, methanesulfonyl chloride, ethyl chloroformate, isobutyl chloroformate and the like in the presence of a base such as triethylamine.
- a base such as triethylamine.
- methylene chloride, chloroform, THF, DMF or the like can be suitably used as a single or mixed solvent. This reaction preferably proceeds at ⁇ 78 ° C. to 100 ° C., more preferably at ⁇ 25 ° C. to 25 ° C.
- reaction of the acid chloride or mixed acid anhydride of compound VI thus obtained with compound VII is preferably -78 ° C in the presence of a base such as pyridine, triethylamine, N, N-dimethylaminopyridine, diisopropylethylamine and the like.
- a base such as pyridine, triethylamine, N, N-dimethylaminopyridine, diisopropylethylamine and the like.
- the reaction proceeds at -100 ° C, more preferably at -25 ° C to 25 ° C.
- the solvent methylene chloride, chloroform, THF, DMF or the like can be suitably used as a single or mixed solvent.
- the reaction from compound VI to compound VIII can also be carried out in the presence or absence of a condensing agent in a suitable solvent by using any conventional method for amide formation commonly used in peptide synthesis and the like. can do.
- a condensing agent N-ethyl-N ′-(3-diethylaminopropyl) carbodiimide, N, N′-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carbonyldiimidazole, diphenylphosphoryl azide Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, fluoro- Any of N, N, N ′, N′-tetramethylformamidinium hexafluorophosphate and
- the solvent water, methanol, isopropanol, ethanol, methylene chloride, THF, dioxane, DMF, dimethylacetamide, chloroform and the like can be suitably used as a single or mixed solvent.
- This reaction preferably proceeds at ⁇ 78 ° C. to 100 ° C., more preferably at ⁇ 25 ° C. to 25 ° C.
- an inorganic base such as potassium carbonate, sodium carbonate or sodium hydrogen carbonate or an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, picoline or lutidine is added as an additive.
- N-hydroxysuccinimide, 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N, N-dimethylaminopyridine, N-hydroxybenzotriazole, etc. Can be promoted.
- the salt of compound VIII can be produced by a commonly used technique.
- the pharmacologically acceptable salt of compound VIII include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide. Or organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate.
- examples of the salt include salts with bases such as alkali metal salts such as sodium salt or potassium salt or alkaline earth metal salts such as calcium salt. It is done.
- the functional groups possessed by the compounds (E) -I, (Z) -I, II and IV to VIII can be converted into functional groups by commonly used techniques.
- the present invention has the following effects. (In the formula, each symbol is the same as above.)
- the crystal of compound (E) -I is precipitated and moved out of the reaction system to shift the isomerization equilibrium.
- the crystals of compound (E) -I can be produced in high yield.
- compound (E) -I which is an intermediate of the oxime derivative represented by formula VIII having GK activating action, can be produced in a single step consisting of simple operations. It was possible to produce in a yield. This made it possible to manufacture industrial quantities safely.
- compound (E) -I can be obtained under mild conditions that do not require the use of trifluoroacetic acid as a solvent, this method is excellent in safety.
- Alkyl includes, for example, C 1-6 , preferably C 1-4 linear or branched alkyl, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -Methylpropyl, pentyl, hexyl and the like.
- Alkoxy includes, for example, C 1-6 , preferably C 1-4 linear or branched alkoxy, and specifically includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Examples thereof include tert-butoxy, pentyloxy, hexyloxy and the like.
- Halogen includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
- Alkanoyl includes, for example, C 1-6 , preferably C 1-4 linear or branched alkanoyl. Specific examples include formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl and the like. Can be mentioned.
- Alkenyl includes, for example, C 2-6 , preferably C 2-4 linear or branched alkenyl, specifically vinyl, allyl, 1-methyl-2-propenyl, 3- Examples include butenyl, 2-pentenyl, 3-hexenyl and the like.
- cycloalkyl in “cycloalkyl” or “cycloalkylcarbonyl” examples include C 3-8 , preferably C 3-6 cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- aryl of “aryl”, “aryloxy” or “arylcarbonyl” for example, C 6-14 monocyclic, bicyclic or tricyclic aryl, preferably C 6-10 monocyclic Or bicyclic aryl is mentioned. Specific examples include phenyl, naphthyl, phenanthryl, anthryl and the like.
- heterocyclic group includes, for example, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a part or all of the 3 to 12 members as a whole may be saturated.
- examples include cycloaliphatic heterocyclic groups, bicyclic heterocyclic groups, and heteroaryl.
- the “monocyclic aliphatic heterocyclic group” it contains 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and is a 3 to 12 member, preferably 4 to 7 member as a whole.
- Preferred examples include aliphatic heterocyclic groups partially or wholly saturated.
- bicyclic heterocyclic group includes a bicyclic heterocyclic group in which the same or different monocyclic aliphatic heterocyclic rings are condensed, the above monocyclic aliphatic heterocyclic group and a benzene ring, a monocyclic hetero ring.
- Examples thereof include a bicyclic heterocyclic group condensed with an aryl or cycloalkane, or a bicyclic heterocyclic group condensed with a monocyclic heteroaryl and a cycloalkane.
- Specific examples of the bicyclic heterocyclic group include indolyl, isoindolyl, tetrahydroquinolyl, tetrahydrobenzofuranyl, tetrahydrobenzopyranyl and the like.
- the “aliphatic heterocyclic group” includes monocyclic aliphatic heterocyclic groups and bicyclic heterocyclic groups.
- Heteroaryl is an aromatic cyclic group having at least one heteroatom (eg, nitrogen, oxygen or sulfur) and a carbon atom, a 5- to 6-membered monocyclic compound, the same or different monocyclic compounds. It includes an 8- to 10-membered bicyclic group in which a cyclic heteroaromatic ring is condensed, and an 8- to 10-membered bicyclic group in which a monocyclic heteroaromatic ring and benzene are condensed.
- heteroatom eg, nitrogen, oxygen or sulfur
- heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, indolyl, indazolyl, Benzimidazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl and the like.
- the L group represents a leaving group, and preferably includes a hydroxyl group, halogen, sulfonyloxy which may be substituted with halogen, aryloxy which may be substituted, etc., specifically, chlorine atom, bromine Atoms, iodine atoms, methanesulfonyloxy, trifluorosulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy and the like can be mentioned.
- the R group is a protective group that hardly undergoes hydrolysis under acidic conditions, and examples thereof include optionally substituted alkyl or alkenyl.
- Preferred examples include alkyl or alkenyl optionally substituted with halogen or aryl, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, benzyl, and allyl. Methyl and ethyl. In particular, methyl is preferred.
- each symbol will be described according to each symbol (R 1 to R 6 , Q, T) in this specification.
- the groups of these symbols can have the same or different 1 to 3 substituents selected from the groups defined below.
- Preferable R 1 includes hydrogen.
- Preferred substituents for substituted alkylsulfonyl in R 2 are 1 or 2 groups selected from alkoxycarbonyl, alkoxy, cycloalkyl (preferably cyclopropyl), hydroxy, substituted or unsubstituted amino (substituent: alkyl, alkanoyl) ), Substituted or unsubstituted heteroaryl (preferably imidazolyl, triazolyl) (substituent: alkyl), alkylsulfonyl, cyano, substituted or unsubstituted heterocyclic group (preferably tetrahydrofuryl, tetrahydropyranyl, dihydro-3H-isoindolyl) (Substituents: oxo, dioxo).
- alkoxy, cycloalkyl (preferably cyclopropyl), and hydroxy are more preferable, and alkoxy is particularly preferable.
- Preferred substituents for substituted alkylthio in R 2 include alkoxy, cycloalkyl, alkoxycarbonyl, hydroxy, cyano, alkylthio, substituted or unsubstituted heterocyclic groups (preferably tetrahydrofuryl, tetrahydropyranyl, dihydro-3H-isoindolyl) (Substituents: oxo, dioxo), heteroaryl (preferably pyridyl). Of these, alkoxy, cycloalkyl, alkoxycarbonyl, hydroxy, cyano, alkylthio, and heteroaryl (preferably pyridyl) are more preferable.
- Preferred substituents of the substituted alkyl which is a substituent of the substituted aminosulfonyl in R 2 include amino optionally substituted with mono- or dialkyl; carbamoyl optionally substituted with mono- or dialkyl; hydroxy; alkoxy; Heteroaryl optionally substituted with alkyl; cycloalkyl; alkoxycarbonyl; hydroxyalkoxy; heterocyclic group optionally substituted with alkyl; halogen atom; alkylthio.
- amino optionally substituted with mono or dialkyl as appropriate; carbamoyl optionally substituted with mono or dialkyl; hydroxy; alkoxy; cycloalkyl; alkoxycarbonyl; heterocycle optionally substituted with alkyl Group; a halogen atom is more preferred, and hydroxy and alkoxy are particularly preferred.
- a preferable substituent of the substituted heterocyclic group which is a substituent of the substituted aminosulfonyl in R 2 includes alkyl.
- Preferred substituents for substituted heterocyclic thio in R 2 include hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl. Aminosulfonyl optionally substituted with mono or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; carbamoyl optionally substituted with mono- or dialkyl; oxo; alkoxy; alkoxyalkyl is more preferable, and alkyl is particularly preferable.
- Preferred substituents for substituted heterocyclic sulfonyl in R 2 are hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl. Aminosulfonyl optionally substituted with mono or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; carbamoyl optionally substituted with mono- or dialkyl; oxo; alkoxy; alkoxyalkyl are more preferable.
- a preferable substituent of the substituted heteroarylsulfonyl in R 2 includes alkyl.
- Preferred substituents for substituted alkoxy for R 2 include cycloalkyl.
- Preferable substituents of the substituted heterocyclic group in R 3 and R 4 include alkoxycarbonyl, oxo, alkyl, and alkanoyl.
- Preferred substituents for substituted heteroaryl in R 3 and R 4 include alkyl; amino optionally substituted with mono or dialkyl. Of these, alkyl is more preferred.
- Preferred substituents for substituted cycloalkyl in R 3 and R 4 include benzoyloxy, oxo, hydroxy, alkanoyl. Of these, oxo and hydroxy are more preferable.
- substituents for substituted aryl in R 3 and R 4 include alkyl, cyano, halogen atom, and alkoxy.
- Preferable substituents of the substituted carbamoyl in R 3 and R 4 include alkyl.
- Preferable substituents for substituted aryloxy in R 3 and R 4 include alkyl, cyano, halogen atom, and alkoxy.
- Preferable substituents for substituted arylcarbonyloxy in R 3 and R 4 include alkyl, cyano, halogen atom, and alkoxy.
- Preferred substituents for substituted alkoxy in R 5 are substituted or unsubstituted amino (substituent: 1 or 2 groups selected from alkyl or alkoxycarbonyl); alkoxycarbonyl; optionally substituted with mono or dialkyl Carboxamoyl; carboxyl; hydroxy; substituted or unsubstituted heterocyclic group (substituent: oxo); trialkylsilyloxy; alkoxy.
- amino optionally substituted with mono or dialkyl as appropriate carbamoyl optionally substituted with mono or dialkyl; hydroxy is more preferred, and amino optionally substituted with mono or dialkyl as appropriate; hydroxy preferable.
- substituents of substituted aminosulfonyl in R 5 include alkyl.
- the alkyl group is monoalkyl or dialkyl, preferably dialkyl.
- Preferred substituents for substituted alkylthio in R 5 include amino optionally substituted with mono or dialkyl; alkoxycarbonylamino; halogen atom; hydroxy; carboxyl; carbamoyl optionally substituted with mono or dialkyl; alkoxy And carbonyl. Of these, amino optionally substituted with mono or dialkyl; alkoxycarbonylamino; hydroxy; carbamoyl optionally substituted with mono or dialkyl is more preferable, and dialkylcarbamoyl is particularly preferable.
- a preferable substituent of the substituted heterocyclic sulfonyl in R 5 includes alkyl.
- Preferable substituents of substituted cycloalkyl in R 5 include amino optionally substituted with mono- or dialkyl.
- a preferred substituent of the substituted carbamoyl in R 5 is selected from substituted or unsubstituted alkyl (substituent: hydroxy; cycloalkyl; heterocyclic group; amino optionally substituted with mono- or dialkyl; heteroaryl) Or 2 groups), cycloalkyl, and heteroaryl.
- substituted or unsubstituted alkyl substituted or unsubstituted alkyl (substituent: 1 or 2 groups selected from hydroxy, heterocyclic group, dialkylamino, heteroaryl) and cycloalkyl are more preferable.
- Preferred substituents for substituted heteroarylthio in R 5 include alkyl.
- substituents of substituted amino in R 5 include alkyl, substituted or unsubstituted aminoalkyl (substituent: 1 or 2 groups selected from alkyl and alkanoyl), alkanoyl, hydroxyalkyl and alkoxycarbonyl. Of these, alkyl, and therefore monoalkyl or dialkyl is more preferable, and dialkyl is particularly preferable.
- Preferred substituents for substituted heteroaryl in R 5 include alkyl.
- Preferred substituents for substituted alkynyl at R 5 include hydroxy, amino optionally substituted with mono or dialkyl. Of these, hydroxy and dialkylamino are more preferred.
- Preferred substituents for substituted heterocyclic carbonyl in R 5 include hydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. Of these, hydroxy, alkyl, and hydroxyalkyl are more preferable.
- Preferred substituents for substituted heterocyclic oxy for R 5 include hydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. Of these, alkyl and oxo are more preferable.
- substituents of the substituted heterocyclic group for R 5 include hydroxy, alkyl, oxo, hydroxyalkyl, and alkanoyl. Of these, oxo is more preferred.
- Preferred substituents for substituted heterocyclic thio in R 5 include hydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. Of these, alkyl and alkanoyl are more preferred.
- Preferable substituents of substituted cycloalkyloxy for R 5 include amino optionally substituted with mono- or dialkyl.
- Preferred substituents for substituted alkyl in R 5 and R 6 include substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted carbamoyl, hydroxy, trialkylsilyloxy, substituted or Examples thereof include unsubstituted alkylthio, substituted or unsubstituted heterocyclic oxy, heteroaryl, substituted or unsubstituted hydroxyimino, and halogen atom, and more preferably substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy , Hydroxy, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted hydroxyimino, halogen atom, more preferably substituted or unsubstituted heterocyclic group
- Preferred substituents of the substituted heterocyclic group which is a substituent of the substituted alkyl in R 5 and R 6 are alkyl; oxo; alkoxyalkanoyl; alkanoyl; alkoxy; alkanoylamino; cycloalkylcarbonylamino; tri (halogeno) alkanoylamino; Formylamino; alkoxycarbonylamino; hydroxy; cycloalkylcarbonyl; tri (halogeno) alkyl; alkoxycarbonyl; formyl; amino optionally substituted with mono or dialkyl; aminosulfonyl optionally substituted with mono or dialkyl Alkylsulfonyl; heteroaryl; alkoxycarbonylalkyl; alkanoyloxyalkanoyl; alkoxycarbonylcarbonyl; optionally substituted with mono- or dialkyl Substituted or unsubstituted carbamoyl (substituent:
- Preferred substituents of substituted amino which is a substituent of substituted alkyl in R 5 and R 6 include alkyl; carbamoylalkyl optionally substituted with mono- or dialkyl; substituted or unsubstituted aminoalkyl (substituent: alkyl, 1 or 2 groups selected from alkanoyl); alkoxyalkyl; hydroxyalkyl; alkoxyalkanoyl; heteroaryl; heteroarylalkyl. Of these, alkyl; carbamoylalkyl optionally substituted with mono or dialkyl; aminoalkyl optionally substituted with mono or dialkyl; alkoxyalkyl; heteroaryl is more preferable, and alkyl is particularly preferable.
- substituents of the substituted alkoxy which is a substituent of the substituted alkyl in R 5 and R 6 include hydroxy and alkoxy.
- Preferable substituents of the substituted carbamoyl which is a substituent of the substituted alkyl in R 5 and R 6 include alkyl and alkoxy.
- substituents of the substituted heterocyclic oxy that is a substituent of the substituted alkyl in R 5 and R 6 include alkanoyl, alkyl, formyl, cycloalkylcarbonyl, alkoxyalkanoyl, and alkylsulfonyl. Of these, alkanoyl and alkyl are more preferable, and alkanoyl is particularly preferable.
- a preferable substituent of the substituted hydroxyimino which is a substituent of the substituted alkyl in R 5 and R 6 includes alkoxycarbonyl.
- cycloalkyl examples include 5 to 6-membered monocyclic cycloalkyl, specifically, cyclopentyl, cyclohexyl and the like, with cyclopentyl being particularly preferable.
- heterocyclic group for example, a 4- to 6-membered monocyclic hetero ring which may have 1 to 3 heteroatoms independently selected from, for example, an oxygen atom, a sulfur atom and a nitrogen atom
- a cyclic group specifically, oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl and the like, and tetrahydrofuryl is particularly preferable.
- heteroaryl in the ring T, for example, a 5- to 9-membered monocyclic or dicyclic which may have 1 to 3 heteroatoms independently selected from, for example, an oxygen atom, a sulfur atom and a nitrogen atom
- heteroaryl examples thereof include cyclic heteroaryl, and specific examples include thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl, quinolyl and the like.
- thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl are preferable, and thiazolyl, thiadiazolyl, pyrazinyl, thiazolopyridinyl, thiazolopyrazinyl In particular, thiazolyl, thiazolopyridinyl, and more particularly thiazolyl are preferable.
- heterocyclic group in the ring T, for example, a 5- to 9-membered monocyclic group optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, or
- a bicyclic heterocyclic group is exemplified, and preferably a 9-membered bicyclic heterocyclic group, specifically, cyclohexanothiazolyl, dihydrothiazolopyridinyl and the like.
- preferable examples include cycloalkylsulfonyl in which R is methyl, R 1 is hydrogen, and R 2 is substituted at the para position with respect to the carbon atom to which the imino group is bonded.
- Example 1 Methanol (3 mL) was added to Compound 1 (1.00 g), and the mixture was heated to 50 ° C. and dissolved. Then, NH 2 OH ⁇ 1 / 2H 2 SO 4 (0.428 g) was added and stirred at 50 ° C. for 2.5 hours. did. Then, it cooled to about 30 degreeC, concentrated hydrochloric acid (5 equivalent) was added, it stirred for 1 hour, the seed crystal of the compound 2 was inoculated, and it stirred at the same temperature for 20 hours. The precipitate was collected by filtration, washed with a methanol / water mixture, and then vacuum-dried to obtain compound 2 (yield 83%, HPLC: purity 98.07%, retention time 11.818 minutes).
- Example 2 Methanol (3 mL) was added to Compound 1 (1.00 g), and the mixture was heated to 50 ° C. and dissolved, and then water (1.5 ml) and NH 2 OH ⁇ 1 / 2H 2 SO 4 (0.428 g) were added to 50 ° C. And stirred for 2.5 hours. Then, it cooled to about 30 degreeC, concentrated hydrochloric acid (5 equivalent) was added, it stirred for 1 hour, the seed crystal of the compound 2 was inoculated, and it stirred at the same temperature for 20 hours. The precipitate was collected by filtration, washed with a methanol / water mixture, and then vacuum-dried to obtain Compound 2 (yield 96%, HPLC: purity 97.55%, retention time 11.842 minutes).
- (E) -hydroxyiminophenylacetic acid derivatives useful for the synthesis of oxime derivatives can be produced industrially.
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Abstract
Description
で示される化合物)を製造中間体として用いるオキシム誘導体の製法が開示されている。しかしながら、ヒドロキシイミノフェニル酢酸誘導体は、幾何異性体の混合物として得られるため、トリフルオロ酢酸(TFA)を溶媒として用いて異性化させ、抽出した後、再結晶を経て(E)-ヒドロキシイミノフェニル酢酸誘導体が製造されており(特許文献1の実施例1)、工程数の少ない、安全な、(E)-ヒドロキシイミノフェニル酢酸誘導体の製造方法の開発が望まれていた。
(1) 式(Z)-I:
R1は水素原子又はハロゲン原子を表し、
R2はハロゲン原子、シクロアルキルスルホニル、置換若しくは非置換アルキルスルホニル、置換若しくは非置換アルキルチオ、置換若しくは非置換アミノスルホニル、置換若しくは非置換非芳香族へテロ環チオ、置換若しくは非置換非芳香族へテロ環スルホニル、置換若しくは非置換へテロアリールスルホニル、アルケニルオキシ、置換若しくは非置換アルコキシ、又は置換若しくは非置換へテロアリールチオを表す。)
で示される化合物を、溶媒中、酸共存下で異性化させ、式(E)-I:
で示される化合物の結晶を析出させることを特徴とする式(E)-Iで示される化合物を製造する方法。
(工程b)式(Z)-I:
で示される化合物を、溶媒中、酸共存下で異性化させ、式(E)-Iで示される化合物の結晶を析出させる工程;及び
(工程c)式(E)-Iで示される化合物の結晶をろ過する工程。
R3及びR4は、独立して水素原子、アルコキシ、置換若しくは非置換ヘテロ環基、アルコキシアルコキシ、置換若しくは非置換シクロアルキル、シアノ、置換若しくは非置換アリール、置換若しくは非置換カルバモイル、ヒドロキシ、アルカノイル、アルキルチオ、アルコキシカルボニル、置換若しくは非置換アリールオキシ、ハロゲン原子、オキソ又は置換若しくは非置換アリールカルボニルオキシを表し、
環Tは、ヘテロアリール又は非芳香族へテロ環基を表し、
R5は水素原子、ホルミル、ハロゲン原子、オキソ、置換若しくは非置換アルコキシ、置換若しくは非置換アミノスルホニル、置換若しくは非置換アルキルチオ、シアノ、置換若しくは非置換非芳香族へテロ環スルホニル、ニトロ、置換若しくは非置換シクロアルキル、アルコキシカルボニル、アルケニル、アルキルスルホニル、置換若しくは非置換カルバモイル、置換若しくは非置換ヘテロアリールチオ、置換若しくは非置換アミノ、カルボキシル、置換若しくは非置換へテロアリール、置換若しくは非置換アルキニル、置換若しくは非置換非芳香族へテロ環カルボニル、置換若しくは非置換非芳香族へテロ環オキシ、置換若しくは非置換非芳香族へテロ環基、置換若しくは非置換非芳香族へテロ環チオ、置換若しくは非置換シクロアルキルオキシ、アルカノイル又は置換若しくは非置換アルキルを表し、
R6は水素原子、置換若しくは非置換アルキル、ハロゲン原子又はカルボキシルを表し、
Lは、脱離基を表し、
その他の記号は、前記と同じ。);
(工程a)式IIで示される化合物と、ヒドロキシルアミン又はその塩を、反応させる工程;
(工程b)式(Z)-I:
で示される化合物を、溶媒中、酸共存下で異性化させ、式(E)-Iで示される化合物の結晶を析出させる工程;及び
(工程c)式(E)-Iで示される化合物の結晶をろ過する工程;
(段階3)式Vで示される化合物を加水分解し、式VIで示される化合物を製造する段階;並びに
(段階4)式VIで示される化合物と、式VIIで示される化合物とを反応させる段階。
酸は、無機酸又は有機酸を用いることができ、例えば塩酸、臭化水素酸、硫酸、燐酸、トリフルオロメタンスルホン酸、トシル酸、メシル酸などから選ばれる、1又は複数種の酸が挙げられ、好ましくは塩酸、とりわけ濃塩酸が好適に利用できる。酸は、存在すればよく、好ましくは3当量以上、とりわけ5当量以上加えることが望ましい。
溶媒の量は、化合物(E)-Iが40℃~70℃では溶解しており、0℃~室温ではその結晶が析出する量が好ましく、例えば、溶媒がメタノールの場合は、1~10ml/g、とりわけ3~5ml/gが好ましい。
結晶の析出は、溶媒の量の調整、化合物(E)-Iの溶解度が低い溶媒の添加、冷却、及び/又は、化合物(E)-Iの種晶を加えることによって、好適に実施できる。
化合物(E)-Iの結晶は、溶媒をろ過することにより、高純度に得ることができる。得られた結晶は、適宜、溶媒で洗浄してもよい。
(工程a)式IIで示される化合物と、ヒドロキシルアミン又はその塩を、反応させる工程;
(工程b)式(Z)-I:
で示される化合物を、溶媒中、酸共存下で異性化させ、式(E)-Iで示される化合物の結晶を析出させる工程;及び
(工程c)式(E)-Iで示される化合物の結晶をろ過する工程。
本工程は、化合物IIと、工程bの実施に適当な溶媒中、ヒドロキシルアミン又はその塩(塩酸塩、硫酸塩等)とを反応させることにより、化合物(Z)-I及び化合物(E)-Iの混合物を製造する工程である。本反応は、ケトンをヒドロキシイミノへ変換する任意の常法にて実施することができる。酸の存在下又は非存在下にて実施することができる。本反応は、0℃~70℃、好ましくは40℃~60℃で好適に実施することができる。
工程aの結果、反応液中に、化合物IIおよびヒドロキシルアミン又はその塩、その他不純物等が共存していてもよい。
本工程は、化合物(Z)-Iから、化合物(E)-Iを製造する方法と同様に行うことができる。
本工程は、工程aによって得られた反応液に40℃~60℃で酸を加えた後、0℃~室温へ冷却し、適宜種結晶を接種することによって、好適に実施することができる。
化合物(E)-Iの結晶は、溶媒をろ過することにより、高純度にて得ることができる。得られた結晶は、適宜、溶媒で洗浄してもよい。
(段階1)化合物(E)-Iで示される化合物を製造する段階;
(段階2)式(E)-Iで示される化合物と、式IVで示される化合物とを反応させて、式Vで示される化合物を製造する段階;
(段階3)式Vで示される化合物を加水分解し、式VIで示される化合物を製造する段階;並びに
(段階4)式VIで示される化合物と、式VIIで示される化合物とを反応させる段階。
段階1は、前記、化合物IIから、化合物(E)-Iを製造する方法に従い、実施することができる。
段階2~4は特許文献1に記載されている方法に従い、以下の通り実施することができる。
化合物(E)-Iと、Lが水酸基である化合物IVとの反応は、適当な溶媒(THF、塩化メチレン等)中、トリフェニルホスフィン存在下、活性化剤(ジエチルアゾジカルボキシレート、ジイソプロピルアゾジカルボキシレート等)を用いるか、又はトリフェニルホスフィン非存在下、シアノメチルトリ-n-ブチルホスホラン等を用いること(いわゆる光延反応)により、実施することができる。
また、Lがハロゲン原子、置換されていてもよいアリールスルホニルオキシ又は置換されていてもよいアルキルスルホニルオキシである化合物IVとの反応は、適当な溶媒(アセトン、エタノール、THF、ジメチルスルホキシド、DMF、ジオキサン、N,N-ジメチルアセトアミド、N-メチルピロリドン等又はその混合溶媒)中、炭酸カリウム、カリウムtert-ブトキシド、水素化ナトリウム、炭酸セシウム等の塩基存在下、実施することができる。
化合物Vは、アルコキシカルボニルをカルボキシルに加水分解する任意の常法、例えば適当な溶媒(メタノール、エタノールなどのアルコール系溶媒、又はTHF、ジオキサン、水等、又はその混合溶媒)中、水酸化リチウム、水酸化ナトリウム、炭酸カリウム等で処理してR基を加水分解することにより、化合物VIに変換することができる。
また、Rがベンジルである化合物Vは、接触還元などにより、加水分解することができる。
化合物VIから化合物VIIIへの反応は、化合物VIを酸塩化物又は混合酸無水物等の反応性中間体に変換した後、化合物VIIと反応させることにより実施することができる。酸塩化物への変換は、塩化チオニル、塩化オキザリル、オキシ塩化リン、五塩化リン、又は四塩化炭素存在下のトリフェニルホスフィン等を用いることにより好適に行うことができ、混合酸無水物への変換は、ジフェニルホスホリルクロリド、ジエチルホスホロシアニデート、メタンスルホニルクロリド、クロロ蟻酸エチル、クロロ蟻酸イソブチル等をトリエチルアミン等の塩基の存在下にて用いることにより行うことができる。溶媒として、塩化メチレン、クロロホルム、THF、DMF等を単一又は混合溶媒としていずれも好適に用いることができる。本反応は、好ましくは-78℃~100℃、より好ましくは-25℃~25℃にて進行する。このようにして得られる化合物VIの酸塩化物又は混合酸無水物と化合物VIIとの反応は、ピリジン、トリエチルアミン、N,N-ジメチルアミノピリジン、ジイソプロピルエチルアミン等の塩基存在下、好ましくは-78℃~100℃、より好ましくは-25℃~25℃にて進行し、溶媒として、塩化メチレン、クロロホルム、THF、DMF等を単一又は混合溶媒としていずれも好適に用いることができる。
本発明の方法では、化合物(Z)-Iから化合物(E)-Iへ異性化させつつ、化合物(E)-Iの結晶を析出させ反応系外に出すことによって異性化の平衡を移動させ、化合物(E)-Iの結晶を高収率にて製造することができる。
「アルキル」としては、例えばC1-6、好ましくはC1-4の直鎖又は分枝鎖状のアルキルが挙げられ、具体的には、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、1-メチルプロピル、ペンチル、ヘキシル等が挙げられる。
「アルコキシ」としては、例えばC1-6、好ましくはC1-4の直鎖又は分枝鎖状のアルコキシが挙げられ、具体的には、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、tert-ブトキシ、ペンチルオキシ、ヘキシルオキシ等が挙げられる。
「ハロゲン」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。
「アルカノイル」としては、例えばC1-6、好ましくはC1-4の直鎖又は分枝鎖状のアルカノイルが挙げられ、具体的には、ホルミル、アセチル、プロピオニル、ブチリル、ペンタノイル、ヘキサノイル等が挙げられる。
「アルケニル」としては、例えばC2-6、好ましくはC2-4の直鎖又は分枝鎖状のアルケニルが挙げられ、具体的にはビニル、アリル、1-メチル-2-プロペニル、3-ブテニル、2-ペンテニル、3-ヘキセニル等が挙げられる。
「シクロアルキル」又は「シクロアルキルカルボニル」におけるシクロアルキルとしては、C3-8、好ましくはC3-6のシクロアルキルが挙げられ、具体的にはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等が挙げられる。
「アリール」、「アリールオキシ」、又は「アリールカルボニル」のアリールとしては、例えばC6-14の単環式、二環式又は三環式のアリールが、好ましくはC6-10の単環式又は二環式のアリールが挙げられる。具体的には、フェニル、ナフチル、フェナントリル、アンスリル等が挙げられる。
「単環式脂肪族複素環基」としては、窒素原子、酸素原子および硫黄原子から選ばれる1~4個のヘテロ原子を含有する、全体として3~12員、好ましくは4~7員の一部又は全部が飽和している脂肪族複素環基が好ましい例として挙げられる。具体例としては、オキサゾリニル、ピロリジル、ピペリジル、ピペラジル、モルホリル、テトラヒドロピラニル、テトラヒドロフラニル、イミダゾリジニル、オキサゾリジニル等が挙げられる。
「二環式複素環基」としては、同一又は異なる上記単環式脂肪族複素環が縮合した二環式複素環式基、上記単環式脂肪族複素環基とベンゼン環、単環式ヘテロアリール若しくはシクロアルカンと縮合した二環式複素環式基、あるいは、単環式へテロアリーリルとシクロアルカンが縮合した二環式複素環式基が挙げられる。当該二環式複素環基としては、具体例としてはインドリル、イソインドリル、テトラヒドロキノリル、テトラヒドロベンゾフラニル、テトラヒドロベンゾピラニル等が挙げられる。
「脂肪族複素環基」には、単環式脂肪族複素環基及び二環式複素環基が含まれる。
「ヘテロアリール」としては、少なくとも1個のヘテロ原子(例えば窒素、酸素又は硫黄)と炭素原子を有する芳香族性の環式基であり、5~6員の単環式化合物、同一又は異なる単環式複素芳香環が縮合した8~10員の二環式基、及び、単環式複素芳香環とベンゼンが縮合した8~10員の二環式基を含む。ヘテロアリール基の具体例として、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリル、オキサゾリル、チアゾリル、イソキサゾリル、イソチアゾリル、オキサジアゾリル、チアジアゾリル、フラザニル、ピリジル、ピラジニル、ピリミジル、ピリダジニル、トリアジニル、インドリル、インダゾリル、ベンゾイミダゾリル、プリニル、キノリル、イソキノリル、フタラジニル、キノキサリニル、キナゾリニル、シノリニル、ベンゾフラニル、ベンゾチエニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイソキサゾリル、ベンゾイソチアゾリル等が挙げられる。
L基は、脱離基を表し、好ましくは、水酸基、ハロゲン、ハロゲンで置換されていてもよいスルホニルオキシ、置換されていてもよいアリールオキシなどが挙げられ、具体的には、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ、トリフルオロスルホニルオキシ、ベンゼンスルホニルオキシ、及びトルエンスルホニルオキシなどが挙げられる。
本明細書におけるR1~R6において、「置換アミノ」、「置換アミノスルホニル」、「置換アミノアルキル」、「置換アミノアルカノイル」、「置換カルバモイル」、「置換カルバモイルアルキル」、「置換アルキル」、「置換アルキルチオ」、「置換アルキルスルフィニル」、「置換アルキルスルホニル」、「置換アルコキシ」、「置換アルカノイル」、「置換アルキニル」、「置換シクロアルキル」、「置換シクロアルキルオキシ」、「置換シクロアルキルカルボニル」、「置換シクロアルキルスルホニル」、「置換アリール」、「置換アリールオキシ」、「置換アリールカルボニル」、「置換アリールカルボニルオキシ」、「置換アリールスルホニル」、「置換アリールアルキルカルボニル」、「置換へテロアリール」、「置換へテロアリールチオ」、「置換へテロアリールスルホニル」、「置換へテロアリールアルキル」、「置換ヘテロ環基」、「置換ヘテロ環オキシ」、「置換へテロ環カルボニル」、「置換ヘテロ環チオ」、「置換ヘテロ環スルフィニル」、「置換ヘテロ環スルホニル」、「置換ヒドロキシイミノ」、「置換フェニル」、「置換ピリジル」、「置換チアゾロピリジニル」、「置換ピラジニル」、「置換ピラゾリル」、「置換イミダゾリル」、「置換チアゾリル」、「置換ベンゾチアゾリル」、「置換キノリル」、「置換チアジアゾリル」、「置換ピラゾリル」、「置換チアゾロピラジニル」、「置換チアゾロピリミジニル」、「置換シクロヘキサノチアゾリル」、「置換ジヒドロチアゾロピリジニル」、「置換トリアゾリル」、「置換ピリミジニル」、「置換ピロリジニル」、「置換テトラヒドロフリル」、「置換チアシクロヘキシル」、「置換シクロペンチル」、「置換ピペラジニル」、「置換ピペラジニルスルホニル」、「置換ホモピペラジニル」、「置換ピペリジニル」、「置換モルホリニル」、「置換チオモルホリニル」、「置換ペルヒドロジアゼピニル」及び「置換テトラゾリル」における置換基としては、(1)適宜ヒドロキシ、アルコキシ、アミノ、モノ若しくはジアルキルアミノ、カルバモイル、テトラヒドロフリル又はピリジルで置換されていてもよいアルキル、(2)シクロアルキル、(3)ヒドロキシ、(4)アルコキシ、(5)シアノ、(6)ハロゲン原子、(7)モノ又はジアルキルアミノ、(8)適宜アルカノイル、アルコキシアルカノイル又はアルコキシカルボニルで置換されていてもよいアミノ、(9)ピリジル、(10)カルボキシル、(11)ホルミル、(12)適宜モノ若しくはジアルキルアミノ、ヒドロキシ、アルコキシ又はアルカノイルオキシで置換されていてもよいアルカノイル、(13)シクロアルキルカルボニル、(14)アルコキシカルボニル、(15)オキソ、(16)アルキルスルホニル等が挙げられる。R1~R6基は、上記の基から選択される同一又は異なる1~3の置換基を有することができる。
R5における置換アミノスルホニルの好ましい置換基としては、アルキルが挙げられる。該アルキル基は、モノアルキル又はジアルキルであり、好ましくはジアルキルである。
R5における置換アルキルチオの好ましい置換基としては、適宜モノ若しくはジアルキルで置換されていてもよいアミノ;アルコキシカルボニルアミノ;ハロゲン原子;ヒドロキシ;カルボキシル;適宜モノ若しくはジアルキルで置換されていてもよいカルバモイル;アルコキシカルボニルが挙げられる。このうち、適宜モノ若しくはジアルキルで置換されていてもよいアミノ;アルコキシカルボニルアミノ;ヒドロキシ;適宜モノ若しくはジアルキルで置換されていてもよいカルバモイルがより好ましく、特にジアルキルカルバモイルが好ましい。
R5及びR6における置換アルキルの置換基である置換アミノの好ましい置換基としては、アルキル;適宜モノ若しくはジアルキルで置換されていてもよいカルバモイルアルキル;置換若しくは非置換アミノアルキル(置換基:アルキル、アルカノイルから選択される1又は2の基);アルコキシアルキル;ヒドロキシアルキル;アルコキシアルカノイル;ヘテロアリール;ヘテロアリールアルキルが挙げられる。このうち、アルキル;適宜モノ若しくはジアルキルで置換されていてもよいカルバモイルアルキル;適宜モノ若しくはジアルキルで置換されていてもよいアミノアルキル;アルコキシアルキル;ヘテロアリールがより好ましく、特にアルキルが好ましい。
Claims (5)
- 式(Z)-I:
R1は水素原子又はハロゲン原子を表し、
R2はハロゲン原子、シクロアルキルスルホニル、置換若しくは非置換アルキルスルホニル、置換若しくは非置換アルキルチオ、置換若しくは非置換アミノスルホニル、置換若しくは非置換非芳香族へテロ環チオ、置換若しくは非置換非芳香族へテロ環スルホニル、置換若しくは非置換へテロアリールスルホニル、アルケニルオキシ、置換若しくは非置換アルコキシ、又は置換若しくは非置換へテロアリールチオを表す。)
で示される化合物を、溶媒中、酸共存下で異性化させ、式(E)-I:
で示される化合物の結晶を析出させることを特徴とする式(E)-Iで示される化合物の結晶を製造する方法。 - 溶媒が、アルコール系溶媒又はアルコール系溶媒と水の混合溶媒である、請求項1又は2のいずれか記載の方法。
- 下記段階を含む、式VIIIで示される化合物又はその薬理的に許容し得る塩を製造する方法:
R3及びR4は、独立して水素原子、アルコキシ、置換若しくは非置換ヘテロ環基、アルコキシアルコキシ、置換若しくは非置換シクロアルキル、シアノ、置換若しくは非置換アリール、置換若しくは非置換カルバモイル、ヒドロキシ、アルカノイル、アルキルチオ、アルコキシカルボニル、置換若しくは非置換アリールオキシ、ハロゲン原子、オキソ又は置換若しくは非置換アリールカルボニルオキシを表し、
環Tは、ヘテロアリール又は非芳香族へテロ環基を表し、
R5は水素原子、ホルミル、ハロゲン原子、オキソ、置換若しくは非置換アルコキシ、置換若しくは非置換アミノスルホニル、置換若しくは非置換アルキルチオ、シアノ、置換若しくは非置換非芳香族へテロ環スルホニル、ニトロ、置換若しくは非置換シクロアルキル、アルコキシカルボニル、アルケニル、アルキルスルホニル、置換若しくは非置換カルバモイル、置換若しくは非置換ヘテロアリールチオ、置換若しくは非置換アミノ、カルボキシル、置換若しくは非置換へテロアリール、置換若しくは非置換アルキニル、置換若しくは非置換非芳香族へテロ環カルボニル、置換若しくは非置換非芳香族へテロ環オキシ、置換若しくは非置換非芳香族へテロ環基、置換若しくは非置換非芳香族へテロ環チオ、置換若しくは非置換シクロアルキルオキシ、アルカノイル又は置換若しくは非置換アルキルを表し、
R6は水素原子、置換若しくは非置換アルキル、ハロゲン原子又はカルボキシルを表し、
Lは、脱離基を表し、
その他の記号は、請求項1に定義されるとおりである);
(段階1)下記工程を含む、式(E)-Iで示される化合物を製造する段階:
(工程a)式IIで示される化合物と、ヒドロキシルアミン又はその塩を、反応させる工程;
(工程b)式(Z)-I:
で示される化合物を、溶媒中、酸共存下で異性化させ、式(E)-Iで示される化合物の結晶を析出させる工程;及び、
(工程c)式(E)-Iで示される化合物の結晶をろ過する工程;
(段階2)式(E)-Iで示される化合物と、式IVで示される化合物と反応させて、式Vで示される化合物を製造する段階;
(段階3)式Vで示される化合物を加水分解し、式VIで示される化合物を製造する段階;並びに
(段階4)式VIで示される化合物と、式VIIで示される化合物とを反応させる段階。 - Rがアルキルであり、R1が水素であり、R2がイミノ基の結合する炭素原子に対しパラ位に置換しているシクロプロピルスルホニルである、請求項1~4のいずれか記載の方法。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05286917A (ja) * | 1992-02-05 | 1993-11-02 | Basf Ag | フェニルグリオキシル酸エステルのe−オキシムエーテルを製造する方法 |
JPH0770032A (ja) * | 1994-08-11 | 1995-03-14 | Shionogi & Co Ltd | E−メトキシイミノ酢酸アミドまたはエステルの製造法 |
WO2007007886A1 (en) * | 2005-07-11 | 2007-01-18 | Mitsubishi Tanabe Pharma Corporation | An oxime derivative and preparations thereof |
WO2008084873A1 (ja) * | 2007-01-10 | 2008-07-17 | Mitsubishi Tanabe Pharma Corporation | オキシム誘導体 |
JP2008189659A (ja) * | 2007-01-10 | 2008-08-21 | Mitsubishi Tanabe Pharma Corp | 医薬組成物 |
JP2010018526A (ja) * | 2008-07-09 | 2010-01-28 | Mitsubishi Tanabe Pharma Corp | 医薬組成物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4158015A (en) * | 1978-08-16 | 1979-06-12 | Mobil Oil Corporation | Process for the stereoselective synthesis of the E isomer of aryl alkyl oximes |
US4260555A (en) * | 1979-11-07 | 1981-04-07 | Ciba-Geigy Corporation | Process for the manufacture of cyanooximinonitriles |
CN101353316B (zh) * | 2007-07-27 | 2012-07-25 | 中科院嘉兴中心应用化学分中心 | 一种肟醚异构化的方法 |
-
2011
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05286917A (ja) * | 1992-02-05 | 1993-11-02 | Basf Ag | フェニルグリオキシル酸エステルのe−オキシムエーテルを製造する方法 |
JPH0770032A (ja) * | 1994-08-11 | 1995-03-14 | Shionogi & Co Ltd | E−メトキシイミノ酢酸アミドまたはエステルの製造法 |
WO2007007886A1 (en) * | 2005-07-11 | 2007-01-18 | Mitsubishi Tanabe Pharma Corporation | An oxime derivative and preparations thereof |
WO2008084873A1 (ja) * | 2007-01-10 | 2008-07-17 | Mitsubishi Tanabe Pharma Corporation | オキシム誘導体 |
JP2008189659A (ja) * | 2007-01-10 | 2008-08-21 | Mitsubishi Tanabe Pharma Corp | 医薬組成物 |
JP2010018526A (ja) * | 2008-07-09 | 2010-01-28 | Mitsubishi Tanabe Pharma Corp | 医薬組成物 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018147368A1 (ja) * | 2017-02-08 | 2018-08-16 | 日産化学株式会社 | オキシイミノ化合物の幾何異性体の製造方法 |
US10710977B2 (en) | 2017-02-08 | 2020-07-14 | Nissan Chemical Corporation | Method for producing geometrical isomer of oximino compound |
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